Abstract
Proline cis-trans isomerization have emerged as an effective regulatory mechanism in a wide range of biological processes related to Alzheimer disease and cancer. However, the details of the mechanism still remain to be clarified. The cis-trans isomerization has been observed in an antigen-antibody system, epiregulin (EPR) and its antibody by X-ray crystallography. Anti EPR antibody, 9E5 has a proline at the residue 103 in the third complementarity-determining region of the heavy chain (CDR-H3), which is in the cis conformation for EPR free 9E5 (apo 9E5) and the trans one for the complex of EPR-9E5 obtained from X-ray crystallography (we refer this complex as “trans-Complex”). Because the cis-trans isomerization is known to occur slowly, with the duration ranging from several minutes to hours, we investigated whether EPR forms a stable complex with apo 9E5 before the isomerization occurs. To identify a stable EPR-binding structure with apo 9E5, we conducted extensive binding molecular dynamics (MD) simulations and additional long MD simulations. An EPR-9E5 complex of which the bound structure is highly similar to that of the trans-Complex was found. We refer this complex as “cis-Complex”. We then investigated the structural stability and conformational changes of the cis-Complex. The cis-Complex is stable for at least 4 μs. It is found that the CDR-H3 loop plays important role for the EPR binding process in which the CDR-H3 loop interacts with EPR strongly. The interaction energy between the EPR and 9E5 is lower than that for the trans-Complex by more than 100 kJ/mol. From 10 μs-MD simulations of the cis-Complex, it is also found that the slight conformal changes of the Pro103 occur slowly during 10 μs.
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